The objective of the proposed research is the development of new and unique drugs that will be effective in the treatment of psoriasis by topical application. These drugs will be analogs of cyclic AMP that have been specifically designed to exhibit the necessary pharmacological, metabolic, and pharmacokinetic properties that they must have in order to be effective in the treatment of psoriasis. These analogs will be developed using a tiered approach, i.e., only those analogs that meet certain criteria at each stage of development are further pursued in the next stage. The tier is set up to follow the logical progression of events that would result in a cyclic AMP analog exhibiting an antipsoriatic effect. Only those cyclic AMP analogs that are able to efficiently stimulate epidermal cyclic AMP-dependent protein kinases and that are also resistant to epidermal cyclic nucleotide phosphodiesterases will be considered for entry into the tiered approach. First, stratum corneum penetration by the cyclic AMP analogs will be measured using whole skin in vitro. Next, the pharmacokinetics of epidermal accumulation of the analogs will be studied in mouse skin in vivo. Then, analogs will be assayed for antipsoriatic-like activity using the hairless mouse model. Finally, analogs will be examined for their ability to inhibit the proliferation of human epidermal cells in vitro. The overall result will be cyclic AMP analogs that are candidates for human clinical trials in the treatment of psoriasis.